Aged regulatory T cells protect from autoimmune inflammation despite reduced STAT3 activation and decreased constraint of IL-17 producing T cells
Vincent J. Hurez
These authors contributed equally to this work.
Search for more papers by this authorSuzanne R. Thibodeaux
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorMark J. Kious
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorAijie Liu
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorPeiyi Lin
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorKruthi Murthy
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorSrilakshmi Pandeswara
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorTahiro Shin
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorTyler J. Curiel
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorVincent J. Hurez
These authors contributed equally to this work.
Search for more papers by this authorSuzanne R. Thibodeaux
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorMark J. Kious
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorAijie Liu
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorPeiyi Lin
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorKruthi Murthy
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorSrilakshmi Pandeswara
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorTahiro Shin
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorTyler J. Curiel
Department of Medicine, Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
Search for more papers by this authorSummary
Regulatory T cells (Tregs) are specialized CD4+ T lymphocytes helping defend against autoimmunity and inflammation. Although age is associated with increased inflammation and autoimmunity, few reports address age effects of immune regulation or auto-aggressive T cells. We show here that young and aged naïve CD4+ T cells are equivalently auto-aggressive in vivo in T cell-driven autoimmune colitis. Young and aged CD4+ Tregs equally suppressed age-matched T cell proliferation in vitro and controlled clinical and pathologic T cell-driven autoimmune colitis, suggesting equivalent regulatory function. However, whereas young and aged CD4+ Tregs suppressed interferon (IFN)-γ+ T cells equivalently in this model, aged CD4+ Tregs unexpectedly failed to restrain interleukin (IL)-17+ T cells. Nonetheless, young and aged CD4+ Tregs equally restrained IL-17+ T cells in vivo during acute inflammation, suggesting a chronic inflammation-related defect in aged CD4+ Tregs. In support, aged Tregs expressed reduced STAT3 activation, a defect associated with poor IL-17-producing T cell restraint. Aged naïve mice had markedly increased programmed death (PD)-1+ T cells, but these exhibited no significant auto-aggressive or regulatory functions in T cell-driven colitis. Young CD8+ CD122− T cells induce autoimmune bone marrow failure, but we show that aged CD8+ CD122− T cells do not. These data demonstrate no apparent age-related increase in auto-aggressive T cell behavior, but disclose previously unrecognized functional defects in aged CD4+ Tregs during chronic inflammation. IL-17 can be inflammatory and contributes to certain autoimmune disorders. Reduced aged Treg function during chronic inflammation and reduced IL-17 restraint could contribute to age-related inflammation or autoimmunity.
Supporting Information
Fig. S1 Histological pathology scores of livers (A) and lungs (B) in groups of N = 3 Rag-1−/− mice transferred with 2.5 ´ 105 CD4+ CD25− CD45RBhi T cells from young or aged C57BL/6 mice, or untreated Rag-1−/− mice (Control). Differences between young and aged cell recipients are not significant.
Fig. S2 Histological pathology scores of livers (A) and lungs (B) in Rag-1−/− mice transferred with 5 ´ 105 CD4+ CD25− PD-1+ T cells (PD-1+) or CD4+ CD25− CD45RBhi T cells (CD45RBhi) from aged C57BL/6 mice and sacrificed 56 days later.
Fig. S3 Body weight changes in Rag-1−/− mice transferred with 5 ´ 105 total CD8+ T cells, or CD8+ CD122+ T cells with or without CD4+ CD25hi Tregs (A), or with CD8+ CD122− T cells with or without CD4+ CD25hi Tregs (B) from aged C57BL/6 mice. No difference in peripheral white blood cell counts at 1.5 months (C) and 4.5 months posttransfer (D) of T cells from mice in panels A–B. None of the differences in weight or cell counts was significant between any groups.
Fig. S4. (A) In vitro suppression of aged CD4+ CD25− CD45RBhi T cell (effector) proliferation by aged Tregs or aged CD4+ CD25− PD-1+ T cells. (B) Histological pathology scores of livers and lungs (C) in Rag-1−/− mice transferred with 2.5 ´ 105 young or aged CD4+ CD25− CD45RBhi T cells alone or with 1.25 ´ 105 CD4+ CD25hi age-matched Tregs.
Fig. S5 Histological pathology scores of livers (A) and lungs (B) in Rag-1−/− mice transferred with 1 ´ 106 CD4+ CD25− CD45RBhi T cells alone or with 5 ´ 105 CD4+ CD25− PD-1+ T cells from aged mice.
Fig. S6 Analysis of pSTAT3 in aged and young immune cells. (A) CD4+ Foxp3-RFP− (naïve) T cells. (B) Young and (C) aged CD4+ Foxp3-RFP+ (Tregs), CD4+ Foxp3-RFP− (naïve), CD8+ T cells, and B cells by flow cytometry after stimulation of the cells with indicated concentrations of IL-6.
Fig. S7 Histological pathology scores of livers (A) and lungs (B) in young and aged Foxp3DTR mice were treated with PBS or DT for 7 days and sacrificed the day after.
Fig. S8 CD62L and CD45RB expression in CD4+ CD25− PD-1+(left) or CD4+ CD25− PD-1−(right) T cells. Representative flow cytometry panel of 3 experiments with similar results using n = 10–12 mice/group is shown.
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